Genomic Signatures of Pregnancy-Associated Breast Cancer Epithelia and Stroma and their Regulation by Estrogens and Progesterone

Hormones and Cancer, Jun 2013

Pregnancy-associated breast cancers (PABC) generally present at advanced stages and have a poor prognosis. The reasons are unclear but we hypothesized that the continuous high levels of estrogens and progesterone were involved. We have now carried out a detailed analysis of PABC compared to tumors of age-matched nonpregnant (non-PABC) women. Malignant epithelia and tumor-associated stroma of PABC and non-PABC were isolated by laser capture microdissection and gene expression profiled. Additionally, normal breast epithelia and stroma adjacent to the two tumor types were analyzed. Lastly, subsets of previously identified E- and P-regulated genes were defined in all tissues. We find that PABC signatures cluster with established breast cancer subtypes. Major hormone-regulated genes whose expression correlated with epithelia of PABC dealt with regulation of cell proliferation, metabolism, and tumor aggressiveness, including genes used to predict tumor recurrence. Compared to normal epithelia, a significant number of genes associated with cell cycle processes were enriched in PABC, many of which are hormone regulated. Thus, compared to normal epithelia, many of the genes that were differentially expressed in epithelia of PABC were distinct from those differentially expressed in non-PABC. With regard to the tumor microenvironment, immune-related genes were enriched in tumor-associated stroma of PABC. Compared to normal stroma, PABC-associated stroma overexpressed immune response genes, while genes involved in angiogenesis and extracellular matrix deposition were more commonly downregulated. This suggests that the heightened aggressiveness of PABC may involve a predisposition to metastasis through extracellular matrix degradation, plus angiogenesis independence. Moreover, genes encoding cell proliferative factors, signaling, immunomodulators and cell death, were hormone regulated in stroma. In sum, these analyses demonstrate complex patterns of enrichment and hormonal regulation of genes in PABC and suggest that it may have a distinct biological nature.

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Genomic Signatures of Pregnancy-Associated Breast Cancer Epithelia and Stroma and their Regulation by Estrogens and Progesterone

Djuana M. E. Harvell 0 Jihye Kim 0 Jenean O'Brien 0 Aik-Choon Tan 0 Virginia F. Borges 0 Pepper Schedin 0 Britta M. Jacobsen 0 Kathryn B. Horwitz 0 0 K. B. Horwitz Department of Pathology, University of Colorado Anschutz Medical Campus , Mail Stop 8106, 12801 E. 17th Avenue, Aurora, CO 80045, USA Pregnancy-associated breast cancers (PABC) generally present at advanced stages and have a poor prognosis. The reasons are unclear but we hypothesized that the continuous high levels of estrogens and progesterone were involved. We have now carried out a detailed analysis of PABC compared to tumors of age-matched nonpregnant (non-PABC) women. Malignant epithelia and tumor-associated stroma of PABC and non-PABC were isolated by laser capture microdissection and gene expression profiled. Additionally, normal breast epithelia and stroma adjacent to the two tumor types were analyzed. Lastly, subsets of previously identified E- and P-regulated genes were defined in all tissues. We find that PABC signatures cluster with established breast cancer subtypes. Major hormone-regulated genes whose expression correlated with epithelia of PABC dealt with regulation of cell proliferation, metabolism, and tumor aggressiveness, J. Kim e-mail: J. O'Brien e-mail: A.-C. Tan e-mail: V. F. Borges e-mail: P. Schedin e-mail: - including genes used to predict tumor recurrence. Compared to normal epithelia, a significant number of genes associated with cell cycle processes were enriched in PABC, many of which are hormone regulated. Thus, compared to normal epithelia, many of the genes that were differentially expressed in epithelia of PABC were distinct from those differentially expressed in non-PABC. With regard to the tumor microenvironment, immune-related genes were enriched in tumorassociated stroma of PABC. Compared to normal stroma, PABC-associated stroma overexpressed immune response genes, while genes involved in angiogenesis and extracellular matrix deposition were more commonly downregulated. This suggests that the heightened aggressiveness of PABC may involve a predisposition to metastasis through extracellular matrix degradation, plus angiogenesis independence. Moreover, genes encoding cell proliferative factors, signaling, immunomodulators and cell death, were hormone regulated in stroma. In sum, these analyses demonstrate complex patterns of enrichment and hormonal regulation of genes in PABC and suggest that it may have a distinct biological nature. Pregnancy associated breast cancers (PABC) variably include cases diagnosed during gestation, lactation, within 1 year of delivery, or up to 510 years postpartum [1, 2]. In the European registry, the average age of patients with PABC is 33 years (range, 2347 years) and the median gestation age at diagnosis is 21 weeks [2]. Among all breast cancer patients, 0.23.8 % have a pregnancy-related disease, comprising 1:10,0001:3,000 pregnancies and about 3,500 cases in the USA each year [3]. However, among premenopausal womenthe only population at risk for this overlapthe numbers are much higher, with 1025 % of breast cancers estimated to be pregnancy-associated when defined as pregnant or within 1 year [3]. The postpartum subset of PABC, those diagnosed after, but within 5 years of a completed pregnancy, represents 4050 % of all breast cancer cases under age 45 [1]. Some studies suggest that older maternal age at first pregnancy and a family history or carrying a BRCA2 mutation represent a specific high-risk group for PABC [1]. The most common (7590 %) histologic type of PABC is invasive ductal carcinoma, with the majority of women diagnosed during or immediately following a completed pregnancy, often with advanced stage disease [2]. PABC is also characterized by higher (5689 %) rates of lymph node involvement compared to nonpregnant (non-PABC), agematched women (3855 %) [2]. Estrogen (ER) and progesterone receptors (PR) are often negative (70 % of tumors) in PABC [2]. However whether ER negativity is increased above the rate expected in age-matched non-PABC controls is unclear, and the high negativity rate may reflect cases diagnosed strictly during pregnancy [4]. These tumors may be falsely classified as ER and PR negative due to downregulation of the receptors in the face of high circulating estrogen (E) and progesterone (P) levels. Liganddependent ER and PR downregulation is a well-described phenomenon that paradoxically is a sign of active functional transcription involving the receptors [5]. The influence of concomitant or recent pregnancy on breast cancer prognosis is complex. On the whole, women diagnosed and definitively treated for their breast cancer during pregnancy have no significant differences in survival after adjusting for age and stage at diagnosis, which suggests that pregnancy is not an independent risk factor per se [1, 2]. On the other hand, breast cancers diagnosed during pregnancy tend to have a higher risk for nodal involvement, higher grade, and mo (...truncated)


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Djuana M. E. Harvell, Jihye Kim, Jenean O’Brien, Aik-Choon Tan, Virginia F. Borges, Pepper Schedin, Britta M. Jacobsen, Kathryn B. Horwitz. Genomic Signatures of Pregnancy-Associated Breast Cancer Epithelia and Stroma and their Regulation by Estrogens and Progesterone, Hormones and Cancer, 2013, pp. 140-153, Volume 4, Issue 3, DOI: 10.1007/s12672-013-0136-z