Our research is focused on characterizing the molecular mechanisms governing growth and tumorigenesis of the mammary gland using B-cell Translocation Gene-2 (BTG2)-mediated inhibition of breast cancer cell growth as a model system, with emphasis on determining molecular targets for mechanism-based treatment strategies and identifying potential molecular markers to predict risk and for early disease detection. BTG2 is expressed in many tissues including the mammary epithelium where its expression demonstrates a dynamic pattern of regulation during postnatal morphogenesis. Estrogen (E2) and progestin, which regulate proliferation and differentiation of the mammary gland, suppress BTG2 mRNA and BTG2 in turn suppresses E2-induced transactivation. Expression of BTG2 in cells impairs G1 to S progression by repressing cyclin D1. Consistent with its anti-proliferative function, BTG2 expression is suppressed in prostate cancer, clear cell renal carcinoma and in thymic and mammary tumors arising in SV40T-Ag harboring transgenic mice. In human breast carcinoma, nuclear BTG2 expression was absent in 46% of tumors and loss of expression significantly correlated with tumor grade and size suggesting a functional role for loss of BTG2 in etiology and disease progression of breast cancer. Consistent with its ability to suppress cyclin D1, loss of nuclear BTG2 in ER positive breast carcinoma correlated significantly with cyclin D1 protein overexpression suggesting that BTG2 may be a factor involved in deregulating cyclin D1 expression in human breast cancer.

Cyclin D1 is overexpressed in ~50% of human breast carcinomas through gene amplification and other mechanisms.  Overexpression of cyclin Dl results in abnormal mammary cell proliferation including development of mammary adenocarcinomas. While BTG2 is a negative regulator of cyclin D1, the mouse BTG2 interacting protein, Pin-1, and the Pin1 interacting protein, AIB-1 (steroid receptor coactivator also known as SRC-3, RAC3, TRAM-1, ACTR and p/CIP) have been shown to positively regulate cyclin D1 expression. Both AIB1 and Pin1 are overexpressed in breast tumors. Although a functional interaction between positive and negative regulators of cyclin D1 expression in breast cancer is likely to exist, little is known about the molecular interaction between this network of proteins and how they contribute to breast cancer progression. Using in vitro and in vivo model systems, our laboratory is characterizing the functional interaction between positive regulators of cyclin D1 and BTG2 in regulation of breast cancer cell growth and hormone responsiveness.

In addition to characterizing the role of BTG2 in mammary morphogenesis and tumorigenesis, my laboratory is also actively investigating the effects of TGFß family members, Mullerian Inhibiting Substance (MIS) and activin, on prostate cancer cell growth. MIS, in addition to causing regression of the Müllerian duct, also suppresses the synthesis of testosterone, a key regulator of prostate growth. The inverse correlation between MIS and testosterone levels in males and subsequent evidence that MIS inhibits testosterone production has, for many years, posed the obvious question: Will MIS regulate growth of the prostate, which is dependent on testosterone for this process? Furthermore, recent data demonstrates the presence of MIS receptors and MIS-mediated signaling in cells derived from the prostate. Exposure of prostate cancer cells to MIS inhibited growth in the presence and absence of androgen suggesting that MIS may overcome androgen-independent survival of prostate cancer cells. Hence MIS, unlike other members of the TGFß-family, which act on the prostate predominantly via paracrine and autocrine mode of action, has the potential to target the prostate both indirectly as an endocrine hormone, by suppressing testosterone synthesis, and directly at the cellular level. Moreover, we have also uncovered a mutually antagonistic cross-talk between activin and androgen signaling in the prostate that may provide important insight into progression of prostate cancer to an androgen-independent state. We are exploring more extensively the role of MIS and activin-signaling pathways in prostate development/differentiation, neoplastic transformation, and tumor progression including emergence of androgen independence.

List of Publications for Maheswaran Laboratory